Patent GB-926623-A (GB)
Title: New guanidines and process for their manufacture
IPC: C07D245/02
Filed: 1960-05-13
Abstract: The invention comprises an (N-R-aza-alkyleneimino-lower alkyl)-guanidine in which the aza-alkyleneimino radical contains 3-8 carbon atoms as ring members, R represents an alkyl or alkenyl group containing up to 10 carbon atoms which may be substituted by an etherified hydroxyl group or an amino group or a halogen atom, a cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl, or cycloalkenyl-lower alkyl containing 3-7 ring carbon atoms, a phenyl, naphthyl or pyridyl residue which may be substituted by a lower alkyl, hydroxyl, lower alkoxy, lower alkylene dioxy, amino or halogeno-lower alkyl group or a halogen atom, or a phenyl-alkyl, naphthylalkyl or pyridylalkyl residue which may be substituted in the aromatic portion by lower alkyl, hydroxyl, lower alkoxy, lower alkylenedioxy, amino or halogen-lower alkyl group or a halogen atom and in the alkyl portion by a phenyl radical and the lower alkyl radical separates the guanido from the imino group by 2 to 7 carbon atoms, an acid addition salt, acyl derivative or quaternary ammonium compound thereof, with the proviso that in a (4-methylpiperazino-lower alkyl)-guanidine or an acid addition salt thereof the lower alkyl radical contains 3 to 7 carbon atoms; the preparation thereof by reacting an appropriate (N-R-aza-alkylene-imino) lower alkylamine with an S-lower alkylisothiourea or a salt thereof and if desired acylating the resulting compound and/or forming the quaternary ammonium compound and/or liberating the free base from an acid addition salt or forming an acid addition salt from the free base; and pharmaceutical compositions containing them.  "Lower" in the above definitions indicates the presence of 1 to 7 carbon atoms in the hydrocarbon radical so qualified.  Etherified hydroxyl groups are lower alkoxy, polyalkyleneoxy, the terminal hydroxyl group of which may also be etherified, aryloxy or aralkoxy groups.  Amino groups are free, mono or disubstituted amino groups and include alkyleneimino, oxa-, thia- and azaalkyleneimino residues which contain 4 to 6 ring carbon atoms. Acyl derivatives are formed from lower aliphatic, aromatic, and araliphatic acids which may be substituted by alkyl, cycloalkyl, or lower alkoxy groups or halogen atoms.  N-RAzaalkyleneiminolower alkylamines are prepared either from an N-R-azaalkyleneimine and an esterified cyano-lower alkanol or a lower alkenyl cyanide to form the (N-R-azaalkyleneimino lower alkyl) cyanide which is then reduced or by reacting a compound of the formula <FORM:0926623/IV(a)/1> where X1 and X2 are reactive esterified hydroxyl groups and n1 and n2 are either 3 or 4 with a lower alkylene diamine.  N-methyl-b - (4-methylpiperazino)ethylamine is prepared by reacting 1-methylpiperazine with 2-bromo-ethanol to give 2-(4-methylpiperazino)ethanol, reacting this with thionyl chloride to give 2-(4-methylpiperazino) ethyl chloride and treating this with methylamine.  1-b - Diethylaminoethylpiperazine is obtained from piperazine and b -diethylaminoethyl chloride.  Similarly are prepared 1-benzyl-1,5-diazacyclooctane and 1-benzyl-1,4-diazacycloheptane.  4-Methyl-2,6-cis-dimethyl piperazine is obtained by reacting 2,6-cis-dimethylpiperazine with methyl formate to give 1-formyl-2,6-cis-dimethylpiperazine and reducing this with lithium aluminium hydride.  Pharmaceutical compositions having antihypertensive properties comprise the guanidines of the invention in admixture or in conjunction with a pharmaceutical carrier suitable for enteral or parenteral administration.  The compositions may be formulated as tablets, capsules, dragees, solutions, suspensions or emulsions and may contain auxiliary and/or other therapeutically useful substances.  Specification 926,624 is referred to.